Loren van der Hoeven^1,2,3,4, Tessa Slagboom^2,3,5 Arjan Malekzadeh⁶, Jantien Hoogmoed^2,4,7, Madeleine Drent^3,5, Eleonora Aronica^2,8, Dirk Jan Stenvers^1,2,3,4,5, Alberto Pereira^1,2,3,4

1. Department of Endocrinology and Metabolism, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
2. Pituitary Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
3. Amsterdam Gastroenterology Endocrinology and Metabolism (AGEM), Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
4. European Reference Network on Rare Endocrine Conditions (Endo-ERN), Amsterdam, the Netherlands
5. Department of Endocrinology and Metabolism, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
6. Amsterdam UMC location University of Amsterdam, Medical Library, Meibergdreef 9, Amsterdam, The Netherlands
7. Department of Neurosurgery, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
8. Department of (Neuro)Pathology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Context:

Immunohistochemistry (IHC) of cell lineage-specific transcription factors (TFs) has been added to the histopathological classification of pituitary adenomas since 2017, resulting in new histopathological subtypes of TF+/hormone– non-functioning pituitary adenomas (NFPAs) and a reduction in the prevalence of null cell adenomas (NCAs).

Objective:

To evaluate associations between the expression of cell lineage-specific TFs by IHC and the radiological presentation and prognosis of NFPAs.

Data sources:

A comprehensive literature search in Medline, Embase, and CENTRAL was performed from inception up to July 11th 2023.

Study selection:

Eligible studies were cohort studies reporting on radiological presentation, recurrence and/or radiotherapy in patients with NFPAs who tested positive for one cell lineage-specific TF or negative for all three of them. Finally, 27 out of 1985 studies were included.

Data extraction:

Two authors independently extracted data and critically appraised risk of bias using the QUIPS tool.

Data synthesis:

Random-effects inverse variance models were used to pool effect sizes. Prevalence rate ratios (PRR) were calculated using the Mantel-Haenszel method. CSI was more prevalent in NCAs and TPIT+ NFPAs compared with SF1+ NFPAs (PRR 1.60 (95% CI 1.22-2.08, p=0.0036), and 1.43 (95% CI 1.21-1.70, p=0.0017), respectively), and in NCAs compared with PIT1+ (PRR 1.44 (95% CI 1.01-2.06, p=0.0454)). Incidence rate ratios per 100 patient years of recurrence and multimodality treatment could not be calculated due to the limited number of studies.

Conclusion:

This review demonstrates that the use of cell lineage-specific transcription factors by IHC enables to detect histopathological subtypes of NFPAs with distinct clinical behaviour.